Repair of infarcted myocardium by skeletal muscle-derived mesenchymal stromal cells delivered by a bioprinted collagen patch.

Mesenchymal stromal cells (MSC) are commonly investigated for post-infarction cardiac repair because of their angiogenic, anti-inflammatory and immunomodulatory properties. However, autologous sources (bone marrow and adipose tissue) require substantially invasive harvest procedures while allogeneic MSC from the cord raise the issue of batch to batch variability. This study assessed the effects of another under-investigated cell source: the skeletal muscle whose autologous MSC feature the clinically appealing advantage of being retrievable by a minimally invasive microbiopsy. MSC differentiated from induced pluripotent stem cells (iPSC) were selected as controls as they also look clinically attractive because of their high scalability and high degree of reproducibility. In vitro, muscle-derived (md) MSC exhibited typical MSC features including a tri-lineage differentiation potential and had robust angiogenic, anti-inflammatory, anti-fibrotic and immune-modulatory effects. Overall, they outperformed iPSC-MSC which raised a safety concern linked to the persistence of some pluripotency-associated markers. They were thus chosen for the subsequent in vivo evaluation in a rat model of left ventricular (LV) dysfunction induced by ischemia/reperfusion. To this end, mdMSC were embedded in a collagen bioprinted gel; the resulting epicardially-delivered patch significantly improved LV ejection fraction compared to a cell-free patch and sham-operated controls. Transcriptomic analysis revealed that this benefit was accompanied by a downregulation of fibrosis-, apoptosis-, and inflammation-related genes. This exploratory proof-of-concept study thus suggests that mdMSC offer an attractive alternative because they combine an autologous origin with a minimally invasive harvest procedure. Bioprinting these cells with a collagen bioink allows to generate a patch endowed with cardio-reparative properties.